The hypothesis of this grant application is that is possible to identify molecular targets in the cancer cell that modify the response of the cell to drugs or radiation and to define the molecular mechanisms that result in such altered sensitivity. On its first submission this grant was entitled "Cell Cycle Targets for Manipulation of Drug and Radiation Sensitivity." On this new submission the title has been slightly altered to be "Molecular Targets for Manipulation of Drug and Radiation Sensitivity." This new title reflects the fact that as we have worked on the grant for the last five years we have come to realize that some factors that we anticipated worked exclusively through cell cycle regulated events in fact have to understood in a wider context involving the regulation of signal transduction and the processes that regulate apoptosis. We are entering a new era in cancer therapeutics. Instead of the traditional approach of nonspecifically and empirically testing cytotoxic agents on a wide variety of tumors, hoping that a suitable candidate might become apparent by serendipity, the new approach is to delineate the molecular mechanisms that promote tumor survival, and then design drugs and treatment regimens that specifically target these mechanisms. This approach has impacted the practice of medical oncology and it is likely that such an approach will also prove fruitful in finding strategies to enhance the efficacy of radiation therapy. The genes ras and p53 have properties that are consistent with the idea that some of the mutational changes in tumor cells alter their response to conventional therapies. Two of the projects we propose will further explore at the basis for the activity of these genes at the molecular level. Two additional projects continue to define at the molecular level the mechanisms of cell cycle checkpoints influencing G2 and cytokinesis since these are the most highly conserved, and thus likely to be the most important, cellular responses to cytotoxic stress. The four projects in this application span a spectrum from investigating signal transduction pathways where targeting agents are already in clinical trial; to pathways clearly involved in sensitivity to drugs and radiation but where agents are not yet ready to proceed to clinical trial, but may soon be ready to go into animals; to very new original studies aimed at identification of additional targets.